RLS is a nervous system disorder, which is thought to be one of the peripheral neuropathies, which gives very uncomfortable abnormal sensation that is a strong itchy sensation on the lower limbs at rest or when falling asleep. Although in some cases, the itchy sensation is also felt on the upper limbs or the trunk, the disorder is characterized by the strong abnormal sensation on the lower limbs as expressed in its name. If RLS is once started, it is impossible to keep the legs still and the patient chafes the soles or moves the legs in order to try to alleviate the symptom even in the slightest degree. In severe cases, the patient cannot keep still on the bed, so that the patient stands up and walks around. Such uncomfortable sensation on the lower limbs cannot be appreciated by those who have not experienced it. According to the complaints by patients themselves, the sensation is often expresses as “itchy” or “as if ants are creeping” (formication). Since RLS often occurs in the night when the patient is falling asleep, the patients cannot keep still, and the falling asleep or the falling asleep in the second time after intermediate awakening is disturbed, so that the patients suffer from severe insomnia. Due to the chronic shortage of sleep, the patients are tired and may suffer from strong fret. Reported pathological states which cause RLS include anemia (iron deficiency anemia), renal failure, uremia, gastrectomy, pregnancy, metabolic diseases (diabetes, porphyria, gout, amyloidosis and the like), infectious diseases (tuberculosis, pneumonia, hepatitis, poliomyelitis and the like), venous thrombosis in lower limbs, drugs (promethazine, prochlorperazine, barbiturates and the like), coldness and psychic factors (Zenji SHIOZAWA et al., Journal of New Remedies & Clinics, Vol. 49, 218-255, 2000).
As the cause of RLS, the publication (NIH Publication No. 00-3788, March 2000) by U.S. National Institute of Health (NIH) suggests secondary onset accompanying the above-mentioned pathological states and familial genetic factors as well as drugs such as tricyclic antidepressants, selective serotonin resorption inhibitors (SSRIs), lithium, dopamine antagonists and caffeine.
Although no survey has been carried out, which precisely measures prevalence of RLS, the prevalence of RLS is estimated to be 2 to 15% in the U.S. based on the total population (NIH Publication No. 00-3788) or 3 to 8% (publication in Japanese by the U.S. RLS Foundation, 1999), 1 to 5% in Europe and 1 to 3% in Japan (Yuichi INOUE et al., Journal of New Remedies & Clinics, Vol. 49, 244-255, 2000). When classified according to the pathological states, the prevalence in the patients suffering from renal failure is extremely high, and is estimated to be about 50% in both the U.S. and Japan (Isao EGAWA et al., New Remedies & Clinics, Vol. 49, 230-235, 2000). RLS is one of the major causes which impair quality of life of the patients. Those which are thought to be symptoms or disorders similar to RLS include periodic limb movements (PLM), myoclonic syndrome, contractions and painful contraction.
Since the cause of RLS has not been well clarified, radical therapy thereof has not been established. In the U.S., there is no drug which was approved by FDA for use against RLS. Although various chemotherapies are now being tried, including those using dopamine agonist, opioid (opioid μ receptor agonist), benzodiazepine, anticonvulsants and the like, they have problems in that the effectiveness is insufficient, sleepiness is carried over until the morning or the effectiveness is reduced with continuous use, so that none of them has been established as a therapeutic method. Opioid drugs which have been applied to RLS include opioid μ receptor agonists such as codeine, hydrocodeine, oxycodone, propoxyphene, tramadol and methadone, and pentazocine which is an opioid μ and κ receptor agonist. However, all of them have insufficient effectivities and problems of side effects or dependency, so that medical satisfactions thereof are poor (NIH Publication No. 00-3788; publication in English by the U.S. RLS Foundation, 2000, Pentagin: U.S. Pat. No. 6,114,326).
In the U.S., RLS Research Foundation was founded. It enlightens the correct understanding of the disease and hints on the life, and supports the research for therapeutic methods.
Thus, in spite of the fact that RLS is very uncomfortable to the patients and decreases the quality of life, the cause thereof has not been clarified and effective therapeutic method has not been established. Thus, RLS is a big problem in medicine and development of more useful therapeutic method is strongly demanded.
It could therefore be advantageous to provide a therapeutic drug for psychoneurotic disorders, which is useful for the therapies of nervous diseases, especially restless legs syndrome.